The promising results seen in studies of secondary bile acids in experimental colitis suggest that they may represent an attractive and safe class of drugs for the treatment of inflammatory bowel diseases (). However, the exact mechanism by which bile therapy confers protection from colitogenesis is currently unknown. Since the gut microbiota plays a crucial role in the pathogenesis of , and exogenous bile administration may affect the community structure of the microbiota, we examined the impact of the secondary bile ursodeoxycholic (UDCA) and its taurine or glycine conjugates on the fecal microbial community structure during experimental colitis. Daily oral administration of UDCA, tauroursodeoxycholic (TUDCA), or glycoursodeoxycholic (GUDCA) equally lowered the severity of dextran sodium sulfate-induced colitis in mice, as evidenced by reduced body weight loss, colonic shortening, and expression of inflammatory cytokines. Illumina sequencing demonstrated that bile therapy during colitis did not restore fecal bacterial richness and diversity. However, bile therapy normalized the colitis-associated increased ratio of to Interestingly, administration of bile acids prevented the loss of cluster XIVa and increased the abundance of , bacterial species known to be particularly decreased in patients. We conclude that UDCA, which is an FDA-approved drug for cholestatic liver disorders, could be an attractive treatment option to reduce dysbiosis and ameliorate inflammation in human . Secondary bile acids are emerging as attractive candidates for the treatment of inflammatory bowel disease. Although bile acids may affect the intestinal microbial community structure, which significantly contributes to the course of these inflammatory disorders, the impact of bile therapy on the fecal microbiota during colitis has not yet been considered. Here, we studied the alterations in the fecal microbial abundance in colitic mice following the administration of secondary bile acids. Our results show that secondary bile acids reduce the severity of colitis and ameliorate colitis-associated fecal dysbiosis at the phylum level. This study indicates that secondary bile acids might act as a safe and effective drug for inflammatory bowel disease.Copyright © 2017 American Society for Microbiology.
Keyword: IBD
Existing methods of clustering of gut microbiota (enterotypes, clusters, gradients), as well as the term 'phylogenetic core' do not reflect its functional activity. The authors propose to describe the key microbiora using term 'phylometabolic core of intestinal microbioca which more accurately reflects the functional importance of metabolically active microbiota. Phylometabolic core includes functional groups of microorganisms that perform similar metabolic functions: butyrate-producing bacteria, propionate-producing bacteria, acetate-produc- ing bacteria (acerogens), hydrogenosrophic microorganisms (reductive acetogens, sulfate-reducing bacteria, methanogens), lactate-producing and lactate-utilizing bacteria, bacteria involved in bile acids metabolism, bacteria that metabolize proteins and amino acids, vitamin-producing microorganisms, oxalate-degrading bacteria and others. The hypothesis that disturbance of microbial metabolism is the root of many human diseases is discussed. The microbial dysmexabo- lism leads to the metabolic dysbiosis (a particular form of dysbiosis) that is primarily characterized by metabolic abnormalities (e.g. serum, urinary, fetal or exhaled air). Metabolic dysbiosis is not necessarily accompanied by appreciable quantitative and/or qualitative changes in microbiora composition that called taxonomic dysbiosis. Since in the metabolic dysbiosis metabolic pathways can be switched only, it means the need for completely different approaches to its assessment using metabolomics (metabolic fingerprinting, metabolic profiling, meta-metabolomics). Metabolites concentrations in colon (feces, biopsy samples), blood (serum, plasma), urine or exhaled air, as well as metabolic profiles of examined substrates can serve as biomarkers. The main clinical variants of metabolic dysbiosis are due to the disturbances in microbial synthesis of short-chain fatty acids (primarily butyrate and propionate) and due to increasing bacterial production of hydrogen sulfide, ammonia and secondary bile acids (particularly ). These kinds of metabolic dysbiosis can eventually lead to inflammatory bowel disease () or colorectal cancer (CRC). The metabolic dysbiosis due to bacterial choline dysmetabolism followed by overproduction of trimethylamine (TMA), arherogenic precursor of trimethylamine N-oxide (TMAO), is associated with atherogenesis and increased risk of cardiovascular disease. Dysmetabolism of aromatic amino acids leads to changes in the microbial production of phenylalanine and tyrosine derivatives (phenyl carboxylic , p-cresol) and tryptophan indole derivatives (indole carboxylic , indole) and contributes to pathogenesis in lBS. , CRC, chronic liver and kidney diseases, cardiovascular diseases, autism and schizophrenia. Metabiotics, a new class of therapeutic agents, e.g. based on microbial metabolites, can correct metabolic dysbiosis, prevent diet- and microbiota-relared diseases and increase the effectiveness of treatment.
Keyword: IBD
Primary sclerosing cholangitis is a rare liver disease which is mainly diagnosed in adults. This chronic progressive disease, characterised by inflammation, fibrosis and strictures of the intra- and extrahepatic bile ducts, leads to cirrhosis. There is a strong association between primary sclerosing cholangitis and inflammatory bowel disease ().A 10-year-old boy presented at the accident and emergency department with fever, episodes of abdominal pain, nausea, vomiting, fatigue and hepatomegaly. Blood tests, pathology investigations, liver biopsy and magnetic resonance cholangiopancreatography (MRCP) led to the diagnosis of primary sclerosing cholangitis. The patient was treated with ursodeoxycholic and later, because of unbearable itching, sequentially with lidocaine 3% ointment, rifampicin, an endoprosthesis in the common bile duct and glucocorticoids. One year later he returned to the paediatrician with abdominal pain and bloody diarrhoea. Endoscopy revealed features of indeterminate colitis. Remission of the disease was achieved quickly after treatment with mesalazine.Primary sclerosing cholangitis can develop in childhood and is often associated with .
Keyword: IBD
The presence of concomitant primary sclerosing cholangitis (PSC) with inflammatory bowel disease () represents a distinct disease phenotype that carries a higher risk of colorectal cancer (CRC) than the average patient. Given that liver transplantation (LT) is the only treatment that offers a survival benefit in PSC patients with hepatic dysfunction, management decisions in patients' post-LT for PSC are frequently encountered. One such consideration is the risk of CRC in this immunosuppressed cohort. With most studies showing an increased risk of CRC post-LT in these patients, a closer look at the associated risk factors of CRC and the adopted surveillance strategies in this subset of patients is warranted. Low-dose ursodeoxycholic has shown a potential chemopreventive effect in PSC- patients pre-LT; however, a favorable effect remains to be seen in post-LT group. Also, further studies are necessary to assess the benefit of 5 aminosalicylate therapy. Annual surveillance colonoscopy in the post-LT period is recommended for PSC- patients subset given their high risk for CRC.© 2018 Crohn’s & Colitis Foundation of America. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
Keyword: IBD
Monocytes are critical to the pathogenesis of inflammatory bowel disease () as they infiltrate the mucosa and release cytokines that drive the inflammatory response. Ursodeoxycholic (UDCA), a naturally occurring bile with anti-inflammatory actions, has been proposed as a potential new therapy for . However, its effects on monocyte function are not yet known. Primary monocytes from healthy volunteers or cultured U937 monocytes were treated with either the proinflammatory cytokine, TNFα (5 ng/ml) or the bacterial endotoxin, lipopolysaccharide (LPS; 1 μg/ml) for 24 h, in the absence or presence of UDCA (25-100 μM). IL-8 release into the supernatant was measured by ELISA. mRNA levels were quantified by qPCR and changes in cell signaling proteins were determined by Western blotting. Toxicity was assessed by measuring lactate dehydrogenase (LDH) release. UDCA treatment significantly attenuated TNFα-, but not LPS-driven, release of IL-8 from both primary and cultured monocytes. UDCA inhibition of TNFα-driven responses was associated with reduced IL-8 mRNA expression. Both TNFα and LPS stimulated NFκB activation in monocytes, while IL-8 release in response to both cytokines was attenuated by an NFκB inhibitor, BMS-345541. Interestingly, UDCA inhibited TNFα-, but not LPS-stimulated, NFκB activation. Finally, TNFα, but not LPS, induced phosphorylation of TNF receptor associated factor (TRAF2), while UDCA cotreatment attenuated this response. We conclude that UDCA specifically inhibits TNFα-induced IL-8 release from monocytes by inhibiting TRAF2 activation. Since such actions would serve to dampen mucosal immune responses in vivo, our data support the therapeutic potential of UDCA for .Copyright © 2016 the American Physiological Society.
Keyword: IBD
We recently have proved that excessive fecal DCA caused by high-fat diet may serve as an endogenous danger-associated molecular pattern to activate NLRP3 inflammasome and thus contributes to the development of inflammatory bowel disease (). Moreover, the effect of DCA on inflammasome activation is mainly mediated through bile receptor sphingosine-1-phosphate receptor 2 (S1PR2); however, the intermediate process remains unclear. Here, we sought to explore the detailed molecular mechanism involved and examine the effect of S1PR2 blockage in a colitis mouse model. In this study, we found that DCA could dose dependently upregulate S1PR2 expression. Meanwhile, DCA-induced NLRP3 inflammasome activation is at least partially achieved through stimulating extracellular regulated protein kinases (ERK) signaling pathway downstream of S1PR2 followed by promoting of lysosomal cathepsin B release. DCA enema significantly aggravated DSS-induced colitis in mice and S1PR2 inhibitor as well as inflammasome inhibition by cathepsin B antagonist substantially reducing the mature IL-1 production and alleviated colonic inflammation superimposed by DCA. Therefore, our findings suggest that S1PR2/ERK1/2/cathepsin B signaling plays a critical role in triggering inflammasome activation by DCA and S1PR2 may represent a new potential therapeutic target for the management of intestinal inflammation in individuals on a high-fat diet.
Keyword: IBD
Bile acids (BAs) are not only digestive surfactants but also important cell signaling molecules, which stimulate several signaling pathways to regulate some important biological processes. The bile--activated nuclear receptor, farnesoid X receptor (FXR), plays a pivotal role in regulating bile , lipid and glucose homeostasis as well as in regulating the inflammatory responses, barrier function and prevention of bacterial translocation in the intestinal tract. As expected, FXR is involved in the pathophysiology of a wide range of diseases of gastrointestinal tract, including inflammatory bowel disease, colorectal cancer and type 2 diabetes. In this review, we discuss current knowledge of the roles of FXR in physiology of the digestive system and the related diseases. Better understanding of the roles of FXR in digestive system will accelerate the development of FXR ligands/modulators for the treatment of digestive system diseases.
Keyword: IBD
Inflammatory bowel disease () is characterized by pain, bleeding, cramping and altered gastrointestinal (GI) function. Changes in mucosal 5-HT (serotonin) signalling occur in animal models of colitis and in humans suffering from . Melatonin is co-released with 5-HT from the mucosa and has a wide variety of actions in the GI tract. Here, we examined how melatonin signalling is affected by colitis and determined how this relates to 5-HT signalling.Using electroanalytical approaches, we investigated how 5-HT release, reuptake and availability as well as melatonin availability are altered in dextran sodium sulfate (DSS)-induced colitis in mice. Studies were conducted to explore if melatonin treatment during active colitis could reduce the severity of colitis.We observed an increase in 5-HT and a decrease in melatonin availability in DSS-induced colitis. A significant reduction in 5-HT reuptake was observed in DSS-induced colitis animals. A reduction in the content of 5-HT was observed, but no difference in tryptophan levels were observed. A reduction in -stimulated 5-HT availability and a significant reduction in mechanically-stimulated 5-HT and melatonin availability were observed in DSS-induced colitis. Orally or rectally administered melatonin once colitis was established did not significantly suppress inflammation.Our data suggest that DSS-induced colitis results in a reduction in melatonin availability and an increase in 5-HT availability, due to a reduction/loss of tryptophan hydroxylase 1 enzyme, 5-HT content and 5-HT transporters. Mechanosensory release was more susceptible to inflammation when compared with chemosensory release.© 2018 The British Pharmacological Society.
Keyword: IBD
The intestinal epithelium constitutes an innate barrier which, upon injury, undergoes self-repair processes known as restitution. Although bile acids are known as important regulators of epithelial function in health and disease, their effects on wound healing processes are not yet clear. Here we set out to investigate the effects of the colonic bile acids, (DCA) and ursodeoxycholic (UDCA), on epithelial restitution. Wound healing in T cell monolayers grown on transparent, permeable supports was assessed over 48 h\u2009with or without bile acids. Cell migration was measured in Boyden chambers. mRNA and protein expression were measured by RT-PCR and Western blotting. DCA (50-150 µM) significantly inhibited wound closure in cultured epithelial monolayers and attenuated cell migration in Boyden chamber assays. DCA also induced nuclear accumulation of the farnesoid X receptor (FXR), whereas an FXR agonist, GW4064 (10 µM), inhibited wound closure. Both DCA and GW4064 attenuated the expression of CFTR Cl channels, whereas inhibition of CFTR activity with either CFTR--172 (10 µM) or GlyH-101 (25 µM) also prevented wound healing. Promoter/reporter assays revealed that FXR-induced downregulation of CFTR is mediated at the transcriptional level. In contrast, UDCA (50-150 µM) enhanced wound healing in vitro and prevented the effects of DCA. Finally, DCA inhibited and UDCA promoted mucosal healing in an in vivo mouse model. In conclusion, these studies suggest bile acids are important regulators of epithelial wound healing and are therefore good targets for development of new drugs to modulate intestinal barrier function in disease treatment. NEW & NOTEWORTHY The secondary bile , , inhibits colonic epithelial wound healing, an effect which appears to be mediated by activation of the nuclear bile receptor, FXR, with subsequent downregulation of CFTR expression and activity. In contrast, ursodeoxycholic promotes wound healing, suggesting it may provide an alternative approach to prevent the losses of barrier function that are associated with mucosal inflammation in patients.
Keyword: IBD
Ursodeoxycholic and lithocholic exert anti-inflammatory actions in the colon. 312: G550-G558, 2017. First published March 30, 2017; doi:10.1152/ajpgi.00256.2016.-Inflammatory bowel diseases () comprise a group of common and debilitating chronic intestinal disorders for which currently available therapies are often unsatisfactory. The naturally occurring secondary bile , ursodeoxycholic (UDCA), has well-established anti-inflammatory and cytoprotective actions and may therefore be effective in treating . We aimed to investigate regulation of colonic inflammatory responses by UDCA and to determine the potential impact of bacterial metabolism on its therapeutic actions. The anti-inflammatory efficacy of UDCA, a nonmetabolizable analog, 6α-methyl-UDCA (6-MUDCA), and its primary colonic metabolite lithocholic (LCA) was assessed in the murine dextran sodium sulfate (DSS) model of mucosal injury. The effects of bile acids on cytokine (TNF-α, IL-6, Il-1β, and IFN-γ) release from cultured colonic epithelial cells and mouse colonic tissue in vivo were investigated. Luminal bile acids were measured by gas chromatography-mass spectrometry. UDCA attenuated release of proinflammatory cytokines from colonic epithelial cells in vitro and was protective against the development of colonic inflammation in vivo. In contrast, although 6-MUDCA mimicked the effects of UDCA on epithelial cytokine release in vitro, it was ineffective in preventing inflammation in the DSS model. In UDCA-treated mice, LCA became the most common colonic bile . Finally, LCA treatment more potently inhibited epithelial cytokine release and protected against DSS-induced mucosal inflammation than did UDCA. These studies identify a new role for the primary metabolite of UDCA, LCA, in preventing colonic inflammation and suggest that microbial metabolism of UDCA is necessary for the full expression of its protective actions. On the basis of its cytoprotective and anti-inflammatory actions, the secondary bile ursodeoxycholic (UDCA) has well-established uses in both traditional and Western medicine. We identify a new role for the primary metabolite of UDCA, lithocholic , as a potent inhibitor of intestinal inflammatory responses, and we present data to suggest that microbial metabolism of UDCA is necessary for the full expression of its protective effects against colonic inflammation.Copyright © 2017 the American Physiological Society.
Keyword: IBD
Inflammatory bowel disease () is thought to arise from an abnormal immune response to the gut microbiota. is associated with altered intestinal microbial community structure and functionality, which may contribute to inflammation and complications such as colon cancer and liver disease. Primary sclerosing cholangitis (PSC) is associated with and markedly increases the risk of colon cancer. We hypothesized that secondary bile acids, which are products of microbial metabolism, are increased in PSC patients.Here, we profiled the fecal bile composition and gut microbiota of participants with and PSC, as well as healthy participants. Additionally, we tested the effects of vancomycin, a proposed treatment for PSC, on gut microbiota and fecal bile composition in participants with and PSC.Fecal samples were collected from patients with , /PSC and healthy controls and fecal bile acids and DNA for microbiota analysis were extracted. Fecal bile acids were averaged over a seven-day period. For subjects with /PSC, oral vancomycin 500mg twice a day was administered and fecal samples were collected for up to eleven weeks.Participants with and PSC had less fecal microbial diversity at baseline relative to controls. While there was some evidence of altered conversion of cholic to , no substantial differences were found in the fecal bile profiles of patients with and PSC (n=7) compared to alone (n=8) or healthy controls (n=8). Oral vancomycin was a potent inhibitor of secondary bile production in participants with and PSC, particularly , although no changes in liver biochemistry patterns were noted over a two week period.In this pilot study, bile profiles were overall similar among patients with and PSC, alone, and healthy controls. Microbiota diversity was reduced in those with PSC and compared to alone or healthy controls.
Keyword: IBD
Colorectal cancer (CRC) is an actual problem today And it occurs 6 times more frequently in patients with inflammatory bowel diseases () than in healthy population. CRC in patients is more aggressive and needs total colectomy, which leads to permanent disability That is why canceroprevention is one of the key goals of treatment. The aim of this review is to overview actual pathogenesis pathways of CRC in and methods of chemoprevention. In this review we describe risk factors of CRC, which can be summarized as aggressive disease and chronic inflammation and are based on pathogenesis of CRC. That is the reason why methods of chemoprevention needs to influence on inflammation and other pathogenesis pathways. The role of such classes of medication as non-steroidal anti-inflammatory drugs, 5-aminosalicylic , immunomodulators, ursodeoxycholic in canceroprevention in RD patients are described in this review.
Keyword: IBD
Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease often leading to end-stage liver disease. Its pathogenesis remains largely unknown, although frequent concomitant hints towards common factors underlying gut and bile duct inflammation. Considering the mounting evidence on the involvement of the intestinal microbiota in initiating and determining phenotype, we investigated intestinal microbiota composition in patients with PSC.Stool samples were collected from 147 individuals (52 patients with PSC, 52 age, gender and body mass index-matched healthy volunteers, 13 UC and 30 patients with Crohn's disease). An independent validation cohort of 14 PSC and 14 matched controls was recruited. 16S rDNA sequencing of faecal DNA was performed (Illumina MiSeq).The microbiota of patients with PSC was characterised by decreased microbiota diversity, and a significant overrepresentation of Enterococcus (p=3.76e-05), Fusobacterium (p=3.76e-05) and Lactobacillus (p=0.0002) genera. This dysbiosis was present in patients with PSC with and without concomitant and was distinct from , and independent of treatment with ursodeoxycholic . A decision tree based on abundances of these three genera allowed reliable classification in the validation cohort. In particular, one operational taxonomic unit belonging to the Enterococcus genus was associated with increased levels of serum alkaline phosphatase (p=0.048), a marker of disease severity.We here present the first report of PSC-associated faecal dysbiosis, independent from signatures, suggesting the intestinal microbiota could be a contributing factor in PSC pathogenesis. Further studies are needed to confirm these findings and assess causality.Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
Keyword: IBD
A westernized high-fat diet (HFD) is associated with the development of inflammatory bowel disease (). High-level fecal (DCA) caused by HFD contributes to the colonic inflammatory injury of ; however, the mechanism concerning the initiation of inflammatory response by DCA remains unclear. In this study, we sought to investigate the role and mechanism of DCA in the induction of inflammation promoting NLRP3 inflammasome activation. Here, we, for the first time, showed that DCA dose-dependently induced NLRP3 inflammasome activation and highly pro-inflammatory cytokine-IL-1β production in macrophages. Mechanistically, DCA-triggered NLRP3 inflammasome activation by promoting cathepsin B release at least partially through sphingosine-1-phosphate receptor 2. Colorectal instillation of DCA significantly increased mature IL-1β level in colonic tissue and exacerbated DSS-induced colitis, while blockage of NLRP3 inflammasome or macrophage depletion dramatically reduced the mature IL-1β production and ameliorated the aggravated inflammatory injury imposed by DCA. Thus, our findings show that high-level fecal DCA may serve as an endogenous danger signal to activate NLRP3 inflammasome and contribute to HFD-related colonic inflammation. NLRP3 inflammasome may represent a new potential therapeutical target for treatment of .
Keyword: IBD